GIGYF1 loss of function is associated with clonal mosaicism and adverse metabolic health

<jats:title>Abstract</jats:title><jats:p>Mosaic loss of chromosome Y (LOY) in leukocytes is the most common form of clonal mosaicism, caused by dysregulation in cell-cycle and DNA damage response pathways. Previous genetic studies have focussed on identifying common variants associated with LOY, which we now extend to rarer, protein-coding variation using exome sequences from 82,277 male UK Biobank participants. We find that loss of function of two genes—<jats:italic>CHEK2</jats:italic> and <jats:italic>GIGYF1</jats:italic>—reach exome-wide significance. Rare alleles in <jats:italic>GIGYF1</jats:italic> have not previously been implicated in any complex trait, but here loss-of-function carriers exhibit six-fold higher susceptibility to LOY (OR = 5.99 [3.04–11.81], p = 1.3 × 10<jats:sup>−10</jats:sup>). These same alleles are also associated with adverse metabolic health, including higher susceptibility to Type 2 Diabetes (OR = 6.10 [3.51–10.61], <jats:italic>p</jats:italic> = 1.8 × 10<jats:sup>−12</jats:sup>), 4 kg higher fat mass (<jats:italic>p</jats:italic> = 1.3 × 10<jats:sup>−4</jats:sup>), 2.32 nmol/L lower serum IGF1 levels (<jats:italic>p</jats:italic> = 1.5 × 10<jats:sup>−4</jats:sup>) and 4.5 kg lower handgrip strength (<jats:italic>p</jats:italic> = 4.7 × 10<jats:sup>−7</jats:sup>) consistent with proposed <jats:italic>GIGYF1</jats:italic> enhancement of insulin and IGF-1 receptor signalling. These associations are mirrored by a common variant nearby associated with the expression of <jats:italic>GIGYF1</jats:italic>. Our observations highlight a potential direct connection between clonal mosaicism and metabolic health.</jats:p>